The goal of this small business innovation research (SBIR) grant is to develop novel compounds that can significantly improve the effectiveness of Type-II diabetes treatment. The need for anti-diabetic drugs is enormous with over 23 million American diabetics and predictions that one-in-three Americans born after 2003 will develop Type-II Diabetes (T2D). New diabetes drugs with fewer side effects and better efficacy are needed as the first line defense drug, metformin, is not tolerated by everyone and only 36% of diabetes patients currently achieve the glycated hemoglobin (HbA1c) goal of d7%. A typical treatment strategy for T2D includes metformin coupled with a PPAR (peroxisome proliferator-activated receptor) agonist (e.g. metformin and Avandia" in Avandamet") plus lifestyle intervention. In a recent illustration of the drawbacks of these drugs, the FDA mandated a black box label for Avandia" (rosiglitazone), a PPAR-3 agonist, due to lethal cardiovascular side effects. The insulin-enhancing incretins (e.g.: exendin/Byetta" GLP-1 mimetics) are a newly approved class of peptide drugs that must be administered by subcutaneous needle injection. The drawbacks for these types of front-line diabetes drugs, PPAR agonists and incretins, are substantial, underscoring the need for novel orally bioavailable PPAR independent drugs. Peroxisomes represent a major site of fatty acid 2-oxidation and the only site of very long-chain fatty acid (VLCFA) 2-oxidation in the cell. Compounds that increase peroxisome biogenesis in rodents universally improve metabolic syndrome and diabetic symptoms and result in decreased elevated plasma fatty acids. Despite the name, however, current PPAR3 drugs do not significantly increase peroxisome biogenesis in humans or rodents. In addition, PPAR-1 agonists (fibrates) that do increase peroxisome biogenesis display superior benefits compared to PPAR-3 agonists (glitazones), which do not. The lipotoxicity hypothesis may help explain these results and states that elevated plasma fatty acids lead to ectopic harmful lipid accumulation in non-adipose tissue, particularly in the liver ("fatty liver") resulting in impaired metabolic function. Our recent technological advances have made possible a high-content/throughput drug discovery pipeline targeting peroxisomal phenotypic endpoints without requiring laborious electron microscopy or histology at the screening stage. This approach has successfully identified a novel non-PPAR peroxisomal proliferator prototype compound with demonstrated significant therapeutic effects in a diet induced obesity (DIO) mouse model of T2D. The proof of principle compound reduces fasting blood glucose, decreases plasma free fatty acids and decreases lipid accumulation in the liver. In this SBIR proposal, we seek to develop compounds that promote peroxisomal/fatty acid oxidizing activity independent of PPARs to provide treatments for T2D by preventing lipid accumulation in non-adipose tissue, decreasing fatty acids in plasma, and increasing insulin sensitivity. Our ultimate goal is to commercialize novel compounds for anti-diabetic therapies. PUBLIC HEALTH RELEVANCE: A typical first treatment strategy for Type-II diabetes (T2D) includes metformin coupled with a PPAR agonist plus lifestyle intervention. The drawbacks for current types of front-line diabetes drugs are substantial and there is a significant need for novel orally bioavailable PPAR independent drugs. We propose to develop novel PPAR-Independent Peroxisome Proliferators for Type 2 Diabetes to address this market need.